Helicobacter pylori

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Helicobacter pylori
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Background

• 1983-discovered by Warren and Marshall in
  Australia
• Discovery revolutionised the treatment of
  duodenal and gastric ulcers
• Earned them the Nobel Prize for Medicine in 2005
• Formerly known as Campylobacter pyloridis

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• Nearly 20 species of Helicobacter are now
  recognised
• The gastric helicobacters colonise the stomachs
  of animals. The monkey, cat, dog, cheetah all
  harbour their own species
• H. cinaedi and H. fennelliae are associated with
  proctitis in homosexual men
• H. pylori are found in the human stomach.
  Molecular studies suggest transmission from an
  animal source.

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Helicobacter pylori
McColl K. N Engl J Med 20103621597-1604
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Description

• Gram-negative spiral bacillus
• Fastidious in terms of growth requirements
• strictly micro-aerophilic
• require C02 for growth
• on charcoal medium
• Has a tuft of sheathed unipolar flagella
  specially adapted to colonise mucous membranes

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Gram stain of H. pylori recovered from an
individual without prior antimicrobial therapy.
Organisms display typical seagull-like
appearance.
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• Hallmark of the species is production of urease
  enzyme
• -urease breaks urea down to C02NH3
• -amonia is a strong base
• -process helps H. pylori survive
• strongly acidic stomach conditions
• Very fragile (a point of importance
• when referring samples to the lab)

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Epidemiology

• H. pylori infection occurs worldwide
• Prevalence varies greatly among countries and
  population groups
• 20 50 prevalence in middle age adults in
  industrialised countries
• gt80 prevalence in middle age adults in
  developing countries
• may reflect poorer living conditions

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Transmission

• Oral ingestion of bacterium
• within families (esp children)
• person-person contact
• faecal-oral transmission
• ?role of water borne transmission
• Usually contracted in the first 2 years of life

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Site of infection

• Highly adapted organism that lives only on
  gastric mucosa
• Gastric antrum is the most favoured site
• Present in the mucus that overlies the mucosa

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Gastric-biopsy specimen showing Helicobacter
pylori adhering to gastric epithelium and
underlying inflammation
McColl K. N Engl J Med 20103621597-1604
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Course of infection

• After several days incubation period, patients
  suffer mild attack of acute gastritis
• -abdominal pain
• -nausea
• -flatulence
• -bad breath
• Symptoms last about 2/52 but hypochlorhydria can
  last up to one year

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• Despite a substantial antibiotic response,
  infection and chronic gastritis persist
• After decades there may be progression to
  atrophic gastritis (conditions which are
  inhospitable for the bacteria) and numbers reduce

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The outcome of infection by H. pylori reflects an
interaction between
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H. pylori infection directly associated with

• PUD
• -lifetime risk 3 in US, 25 Japan
• -eradication provides long-term cure
• Gastric carcinoma
• -strong evidence of increased risk 0.1-3
• -unclear whether eradication reduces the
  risk of gastric cancer
• MALT lymphoma
• -72? 98 of MALT lymphoma infected with H.
  pylori

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Laboratory diagnosisnon-invasive tests

• Serology detect an immune response by examining
  a blood sample for abs to the organism (ELISA)
• poor accuracy
• Urea breath test a urea solution labelled with
  C14 isotope is given to pt. The C02 subsequently
  exhaled by the pt contains the C14 isotope and
  this is measured. A high reading indicates
  presence of H. pylori

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• Faecal antigen test detect H. pylori antigens
  in faecal specimens
• Polymerase chain reaction (PCR) can detect HP
  within a few hours. Not routine in clinical use.

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Invasive testing

• Histological examination of biopsy specimens of
  gastric/duodenal mucosa take at endoscopy
• CLO-test based again on urease-production by
  the organism-gtNH3 production-gtrise in pHgtchange
  in the colour indicator of the kit
• -High sensitivity and specificity
• -Prompt result

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Invasive testing

• Culture
• -no more sensitive than skilled
  microscopy of histological sections
• -used for antibiotic resistance testing
• -requires selective agars and
  incubation periods

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Tests for Helicobacter pylori Infection
McColl K. N Engl J Med 20103621597-1604
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Indications for therapy

• Strongly recommended
• Duodenal or gastric ulcer
• MALT lymphoma
• Atrophic gastritis
• Recent resection of gastric cancer

Maastricht 2-2000 Consensus Report
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Indications for therapy

• Treatment advised
• Functional dyspepsia
• Gastro-oesophageal reflux disease (patients
  requiring long-term acid suppressive therapy)
• Use of NSAIDs

Maastricht 2-2000 Consensus Report
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Treatment

• Goal of treatment to eradicate infection
• Triple therapy regimens consist of one
  anti-secretory agent and two antimicrobial agents
  for 7 to 14 days
• Triple therapy regimens must
• have cure rate of approximately 80
• be without major side effects
• - minimal induction of resistance

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First line treatment

• Combination of two or more antimicrobial agents
  increases rates of cure and reduces the risk of
  selecting for resistant H. pylori
• Many factors may result in failure of treatment
• microbial factors
• patient compliance
• geographical differences

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• First line therapy
• PPI b.d. clarithromycin 500mg b.d.
• amoxicillin 1000mg b.d. or metronidazole 400mg
  BD minimum of 7 days
• In case of failure
• Second line therapy
• PPI b.d. bismuth subsalicylate/subcitrate 120mg
  QDS metronidazole 500mg t.d.s. tetracycline
  500mg q.d.s.
• for a minimum of 7 days
• If bismuth is not available, PPI based triple
  therapies should be used
• Subsequent failures should be handled on a
  case-case basis. Patients failing second-line
  therapy in primary care should be referred

Maastricht 2-2000 Consensus Report
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NEJM 20023471175-86
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Guidelines for Evaluation and Management of
Helicobacter pylori Infection
McColl K. N Engl J Med 20103621597-1604
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Reinfection

• Reinfection following successful bacterial cure
  is unusual
• Commonly represents recrudescence of the original
  bacterial strain
• In adults, reacquisition of the bacteria occurs
  in lt2/persons/year which is similar to the rate
  of primary infection in adults

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Failure of treatment

• Failure of initial course occurs in 1 in 5
• 2nd-line Tx
• either an alternative regimen
• quadruple Tx (PPIbismuth2 antibx)

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Key points

• -gt H. pylori is a flagellated spiral micro-aerobe
• -gt Infection is a risk factor for gastric cancer
• -gt Causes PUD and gastritis
• -gt Produces a cell-damaging toxin
• -gt Transmission route is unclear
• -gt Dz rates are falling in industrialised
  countries
• -gt Tx is by eradication using combination therapy

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Recommendations

• The noninvasive test-and-treat strategy for H.
  pylori infection is reasonable for younger
  patients who have upper gastrointestinal symptoms
  but not alarm symptoms
• Noninvasive testing can be performed with the use
  of the urea breath test, fecal antigen test, or
  serologic test the serologic test is the least
  accurate
• Triple therapy with a proton-pump inhibitor,
  clarithromycin, and amoxicillin or metronidazole
  remains an appropriate first-line therapy
• Recurrence or persistence of symptoms after
  eradication therapy for uninvestigated dyspepsia
  is much less likely to indicate that treatment
  has failed than to indicate that the symptoms are
  unrelated to H. pylori infection.

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Recommendations

• Further eradication therapy should not be
  considered unless persistent H. pylori infection
  is confirmed
• Data are lacking to inform the optimal management
  of recurrent or persistent dyspepsia after
  noninvasive testing and treatment of H. pylori
  infection
• Options include symptomatic acid-inhibitory
  therapy, endoscopy to check for underlying ulcer
  or another cause of symptoms, and repeat of the
  H. pylori test-and-treat strategy other
  potential reasons for the symptoms should also be
  reconsidered

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Clinical Practice Helicobacter pylori Infection
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Amoxicillin resistance

• Amoxicillin resistance rare (0.3-1.4 generally,
  rates as high as 38 have been reported)
• Stable resistance has been reported
• Because H. pylori can exchange DNA through
  natural transformation and also through
  conjugation, spread of amoxicillin resistance
  among H. pylori is potentially a major threat
• ?Restriction of indications for treatment rather
  than indiscriminate eradication of H. pylori

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Risk factors for resistance

• Risk factors for metronidazole resistance
• Sex female gt male
• Ethnicity Asian gt European
• Test method use of E test vs. agar dilution
• Risk factors for clarithromycin resistance
• Geographical region prescribing trends/genotype
• Age increasing age
• Sex female gtmale
• Ulcer status inactive gtactive

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Consumption Resistance

• Perez Aldana et al. 593 Japanese patients
  dyspepsia, no previous triple therapy
• Clarithromycin resistance 7 in 1997/8 to 15 in
  1999/2000
• Metronidazole resistance 6.6 in 1997/8 to 12 in
  1999/2000
• (Amoxicillin resistance reported 0.3)
• Postulated that increase in antibiotic resistance
  was associated with a huge increase in
  clarithromycin use in Japan between 1993 and 2000
• Consumption of metronidazole gradually increased
  during that time
• Rate of resistance to metronidazole low, compared
  to worldwide rates, due to low consumption of
  metronidazole in Japan

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Secondary resistance

• Development of secondary resistance for
  clarithromycin and/or metronidazole may occur in
  50 of cases
• AMNCH study (1997) secondary resistance to
  clarithromycin acquired in 58.3 of strains in
  cases of treatment failure
• Using most effective regimen will help to
  minimise developed of secondary resistance

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Resistance primary secondary

• AMNCH (1997)
• Clarithromycin, metronidazole, omeprazole x 1/52
• Primary resistance MET 35.6, CLA 3.4
• Eradication rate 81.6 overall 98.2 fully
  sensitive isolates 57.1 metronidazole resistant
  strains 0 dual resistant strains
• Secondary resistance to clarithromycin acquired
  in 58.3 of cases of treatment failure

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Antibiotic sensitivity testing

• Excellent eradication rates have been achieved
  when prior resistance to one particular
  antibiotic was known
• Methodological problems- slow growing
  microaerophilic organism (10 14 days) and
  difficulty interpreting susceptibility data
• More than 50 of the population may carry a
  mixture of sensitive and resistant strains in
  non-uniform distribution
• May achieve better results if multiple biopsies
  from several sites are used

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Molecular testing

• Clarithromycin
• Molecular assays detecting 23S rRNA mutation esp.
  PCR-RFLP
• Can be performed on DNA from gastric aspirate or
  biopsy - ?same day results
• Others e.g. DNA enzyme immunoassay (DEIA), PCR
  line probe assay (LiPA)
• LiPA detects seven distinct resistance mutations
  suitable for testing large numbers of people
• LiPA assay H. pylori in West of Ireland
  clarithromycin resistance 27 (not correlated
  with conventional CS)

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• First line therapy
• PPI (RBC) b.d. clarithromycin 500mg b.d.
• amoxicillin 1000mg b.d. or metrodiazole 500md BD
  minimum of 7 days
• In case of failure
• Second line therapy
• PPI b.d. bismuth subsalicylate/subcitrate 120mg
  QDS metronidazole 500mg t.d.s. tetracycline
  500mg q.d.s.
• for a minimum of 7 days
• If bismuth is not available, PPI based triple
  therapies should be used
• Subsequent failures should be handled on a
  case-case basis. Patients failing second-line
  therapy in primary care should be referred

Maastricht 2-2000 Consensus Report
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2nd line treatment

• Quadruple therapies with bismuth, PPI 2
  antibiotics
• Success rate of eradication variable - lt60-100
• Eradication rates dependent on 1st line therapy
  used and primary resistance rates
• 78-80 eradication achieved in an area where
  metronidazole resistance is 40
• AMNCH study(1997) only 57.1 eradication rate
  with metronidazole resistance and 0 (0/3) for
  dual resistance

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Other 2nd line options

• Rescue therapies with rifabutin - promising
  with rates of 78.6 despite multiple therapies
  (resistance H. pylori rpoB gene)
• Stepwise therapies combining triple therapy,
  quadruple therapy, high doses of clarithromycin
  and proton pump inhibitor in a stepwise fashion
  (100 eradication in one series)

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Gram stain of H. pylori recovered from patient,
C.B. following 3 courses of antimicrobial
therapy. Organisms appear enlarged and of
abnormal morphology.
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NEJM 20023471175-86
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Host response to infection

• H. pylori attaches to gastric epithelial cells
  triggering host inflammatory response
• HP infected patients gastric epithelium have
  enhanced levels of IL-1ß, IL-2, IL-6, IL-8, TNFa.
• IL-8 appears to have central role, acting as a
  potent neutrophil activating chemokine

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Host response to infection

• H. pylori attaches to gastric epithelial cells
  triggering host inflammatory response
• H. pylori bind to class II MHC molecules on
  surface of gastric epithelial cells inducing
  apoptosis
• HP urease porins may contribute to
  extravasation chemotaxis of neutrophils
• HP infected patients gastric epithelium have
  enhanced levels of IL-1ß, IL-2, IL-6, IL-8, TNFa
• IL-8 appears to have a central role

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Host response to infection

• Marked systemic mucosal humoral response
  antibodies do not lead to eradication of the
  infection but may contribute to tissue damage
• Th1 response predominates and Th1 cytokines
  promote gastritis may occur due to increased
  IL-8 production
• Th2 response expected (extracellular pathogen)
  does not occur, would protect gastric mucosa

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NEJM 20023471175-86
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Host response

• Most disease causing HP strains are type I
  containing the cag-pathogenicity island (PAI)
• cag-PAI carrying strains induce a much stronger
  IL-8 response than cag-negative
• Proteins encoded by cag-PAI
• induction of IL-8 production of gastric
  epithelial cells
• translocation of CagA protein from bacteria to
  host

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Pathogenesis

• HP genome studies have shown that the genome
  changes continuously during chronic colonisation
  importing small pieces of foreign DNA from other
  HP strains
• Phase variable genes encode proteins including
  enzymes modifiying surface antigens, control the
  entry of foreign DNA into the bacteria and
  influence motility

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Pathogenesis

• Urease production essential for survival urease
  hydolyses urea into carbon dioxide ammonia
  permitting survival in acidic milieu
• Motility essential for colonisation HP flagella
  have adapted to gastric niche.
• Vacuolating cytotoxin (VacA) expressed by
  majority of strains of HP, appears to increase
  bacterial fitness
• Huge variation in VacA strains

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Diagnosis

• Minimally invasive testing
• Urea breath test (UBT) - initial diagnosis
  follow up for eradication sensitivity/specificity
  90
• Serological testing pre-treatment diagnosis of
  HP infection. AMNCH study (2000) 82.4 sensitive
  and 85 specific
• Stool antigen test 89-98 sensitivity gt90
  specificity
• Stool immunoassay PCR under investigation

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Diagnosis

• Endoscopy biopsy indicated-
• Severe symptoms
• Anaemia
• Weight loss
• Patients gt50 years

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Diagnosis

• Urease test (CLO) on biopsy specimen rapid
  detection (sensitivity 79 100, specificity 92
  100)
• Sensitivity of urease test can be improved by
  additional biopsies
• False negatives active or recent bleeding,
  antibiotic or antisecretory therapy
• Histological examination can be performed if
  urease test negative (gt90 sensitive and specific)

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Treatment failure

• Treatment failure may result from-
• Bacterial resistance in theory the most
  important factor in failure of primary treatment
• Poor adherence to antibiotic guidelines
• Patient compliance positive role shown for
  compliance enhancing programmes
• Geographical region bacterial/patient genotype,
  prevelance of resistance, local antibiotic use
• Cost duration of therapy
• Minors- drug metabolism pathways (e.g. CYP2C19
  genotype), intragastric pH, antimicrobial
  stability